In addition to their well-known role in cellular energy metabolism. mitochondria also serve an important role as controllers of programmed cell death (apoptosis). Unregulated apoptosis is the basis for diseases ranging from malignancy to autoimmune diseases and atherosclerosis. The fundamental role of mitochondria in disease states appears to be intimately linked to signaling pathways that exist between mitochondria and the cytoplasm of the cell. Perhaps the most important pathway involves the release of cytochrome c from mitochondria into the cytoplasm, a critical signal for cell apoptosis. However, the mechanisms responsible for the release of cytochrome c from mitochondria remain poorly understood. Therefore, two Specific Aims have been identified for this five-year proposal: 1) To define the relationship between mitochondrial swelling and the release of cytochrome c from isolated mitochondria preparations. 2) To determine the mechanism through which the BCl-2 family protein. BAX, facilitates the release of cytochrome c from mitochondria. Through investigations of mitochondrial apoptotic pathways. this proposal will provide new insights into mitochondrial diseases and will establish the candidate's future in mitochondrial medical research. The Specific Aims of this proposal will define the mechanisms through which mitochondrial membrane pores participate in the release of cytochrome c from mitochondria. In addition, the candidate will develop basic research skills and in-depth understanding of mitochondrial biological processes that will establish him as an independent investigator in the field of mitochondrial medical research. The long-term goal of this proposal is to develop the foundation for a productive career in medical research related to the role of mitochondria in disease, a rapidly growing area of investigation. In this regard, the candidate is fortunate to have established mentorship with highly successful scientists in an environment conducive to his development as an independent investigator. This proposal integrates the pulmonary clinical research expertise of Dr. Mark Wewers with the basic science expertise of Dr. Douglas Pfeiffer, the sponsors of this project. These advisors are actively investigating the role mitochondria in the pathogenesis of disease. Thus, the prospects for successful collaborative initiatives, a critical determinant of future success, are excellent.